Ubiquilin2, is a protein that abnormally accumulates in many
neurodegenerative diseases. Additionally, mutations in UBQLN2 gene
cause a familial frontotemporal dementia (FTD) and amyotrophic
lateral sclerosis (ALS). Normally, ubiqilin2 aids the clearance of
aged or damaged proteins. In case of ubiqilin2 aggregation, the
cellular surveillance that targets protein clearance may be
compromised, in turn causing protein accumulation. Additionally, the
aggregated state of ubiqilin2 may become toxic, thus accelerating
cellular death. Studies of the native and aggregation
state of ubiqilin2 can give insights into protein’s
function and disease mechanism. For the purpose we apply a combination of
biophysical to cellular methods.
Hexanucleotide repeat expansions in C9orf72 are the most
common inherited cause of ALS and FTD. This mutation elicits
toxicity in part through repeat-associated non-AUG (RAN) translation
of the intronic (GGGGCC)n sequence into dipeptide repeat containing
proteins (DPRs). In collaboration with the neurodegenerative disease
group in the Department of Neurology, we established a strong
correlation between peptide structure and toxicity. At present we
focus at structural studies of the toxic aggregates. The goal is to use these
structures for developing molecules that reduce the formation of the toxic
species .
Human genetics, cellular biology and biochemistry, and neurobiology
indicate a causal role for the protein α-synuclein in the
pathogenesis of Parkinson's disease (PD). Lewy bodies (LB), which
consist primarily of aggregated α-synuclein, are found in patients
with PD and Lewy body dementia (DLB). In addition, α-synuclein
accumulates in glial cells in condition known as multiple system
atrophy (MSA). The abnormal accumulation of α-synuclein is now
recognized as a signature of multiple forms of neurodegeneration.
Yet our understanding of the molecular mechanism of aggregation is
still limited. To increase our knowledge in the area, we currently
focus on the studying the structure of α-synuclein fibrils which
were purified from the brains of the individuals affected by PD, DLB
and MSA.